Probing protein flexibility reveals a mechanism for selective promiscuity

Area of Science:

• Structural biology and biophysics
• Computational drug discovery
• Molecular dynamics simulations

Background:

• Eukaryotic regulatory proteins exhibit conformational flexibility, enabling specific binding to multiple partners.
• Understanding the molecular mechanisms behind selective ligand binding remains a challenge.
• The programmed cell death protein 1 (PD-1) receptor and its ligands (PD-L1, PD-L2) are crucial in immune regulation and cancer.

Purpose of the Study:

• To identify and quantify the interactions governing selective protein-ligand binding.
• To investigate the binding pathway of PD-1 with its ligands, PD-L1 and PD-L2.
• To explore a biophysical approach for targeting 'undruggable' proteins.

Main Methods:

• Employed a molecular dynamics approach to analyze protein-ligand interactions.
• Focused on the programmed cell death protein 1 (PD-1) receptor and its interactions with PD-L1 and PD-L2.
• Quantitatively evaluated the specific interactions responsible for selective binding.

Main Results:

• Unbound PD-1 presents a hydrophilic interface that is difficult to drug.
• Ligand-specific triggers in PD-L1 and PD-L2 activate a promiscuous binding pathway, revealing a flexible hydrophobic cavity in PD-1.
• Specificity is achieved through additional contacts that stabilize distinct bound conformations of the PD-1 cavity.

Conclusions:

• Elucidates the structural basis and evolutionary principles behind proteins binding multiple partners.
• Demonstrates how specific triggers in ligands can overcome challenges posed by 'hard-to-drug' protein interfaces.
• Suggests a novel biophysical strategy for developing therapeutics against challenging targets like PD-1.